Analysis and purging of materials in manufacturing processes

ABSTRACT

Various systems and methods of analyzing one or more properties of a sample are provided. The system includes a self-contained purging device having a sample holder and one or more analyzers for analyzing one or more properties of the sample. The purging device is configured to remove sample contained within the sample holder when an analysis is complete. In one embodiment the purging device is configured via an air pump having a tube in fluid communication with an air inlet of the sample holder, wherein the air pump is configured to deliver pressurized air to the air inlet and thereby purge the sample. The pressurized air is localized ambient air, and substantially free of contaminants. Methods and other systems are also described and illustrated.

BACKGROUND 1. Field of the Invention

Embodiments of the invention relate generally to in-process monitoringsystems, and to methods of using such systems. More particularly,disclosed embodiments relate to in-process monitoring systems integratedinto a production line and configured to analyze one or more propertiesof a sample as it is being produced, and methods of using such systems.

2. Description of the Related Art

During the manufacture of pharmaceuticals, fine chemicals, specialtychemicals and the like, a sample of the material is typically removedduring production for testing to ensure that the material meetspre-established requirements. For example, a pharmaceutical powder maybe tested to ensure that a sufficient amount of an active pharmaceuticalingredient is present. The testing of the material is usually performed“off-line,” which can take hours or even days. By the time the testresults are available, production of the material may already have beencompleted. If the test results do not meet specifications, the wholemanufacturing lot must be discarded and must be produced again, whichcan be expensive, both in terms of time expended and wasted materials.Moreover, because there is a separation between the time of the actualmaterial test and the manufacturing process itself, such test resultsmay not be completely useful in assessing the reason for a failure.

Attempts have been made to design a testing device that may beintegrated into the production process so that the material beingproduced is tested or analyzed while (or at substantially the same time)it is being manufactured. However, such attempts have not beensatisfactory, primarily because the resulting devices are inaccurate orintroduce additional problems. For example, such devices typicallyintroduce contaminants into the manufactured material (e.g., by the useof compressed shop air), which causes inaccurate test results.Additionally, existing devices are not adequate because they are onlycapable of performing a subset of the desired tests and the testing ofthe material is incomplete.

SUMMARY

Disclosed embodiments are directed to systems and methods for analyzingsamples in-process, and in substantially in real time. Thus, a materialcan be tested while it is being manufactured or produced. In this way,problems can be detected (and corrected) in a timely fashion, and in thecontext of a given production run. Moreover, disclosed embodimentsprovide the in-process testing in a manner that does not introducecontaminants into the production system.

In one embodiment, a system is provided for analyzing one or moreproperties of a sample of a material being produced in a productionsystem. While the material being produced (and sampled) could include avariety of types, common examples would be pharmaceuticals, finechemicals or specialty chemicals. The example system includes aself-contained purging device having a sample holder and one or moreanalyzers for analyzing one or more properties of a sample of thematerial that is obtained during the production process and placed inthe sample holder. In operation, the system is integrated within theoverall production system such that a sample of the material beingproduced is introduced into the sample holder. The one or more analyzersthen perform a predetermined test on the retrieved sample. While any oneof a number of different tests could be performed, current embodimentscontemplate tests such as spectroscopy, moisture detection ormeasurement, particle size detection, and the like. When completed, theself-contained purging device expunges the sample from the sampleholder. The purging device is “self-contained” in the sense that thepurging function occurs without introducing any foreign materials orother components (excess humidity, oil, shop air, dust and the like)that are “external” to the production system, thereby avoiding theintroduction of any contaminants into the sample holder (which couldaffect subsequent tests) or into the material being produced (whichcould compromise the viability of the production material). Because theproduction system is self contained, it can be used to monitor veryprecise particles over time, such as proteins being generated bybacteria, crystals, DNA, or whole cells.

The purging device can be implemented in a number of different ways. Forexample, in one embodiment the purging device is implemented so as toremove the sample from the sample container by way of pressurized air(or other appropriate gas). This embodiment includes, for example, anair pump having a tube in fluid communication with an air inlet of thesample holder. The air pump is configured to deliver “on demand”pressurized air to the air inlet that is sufficient to completely purgethe material sample from the sample holder. Preferably, the air is“ambient” or localized air that is obtained local to the system and isthereby contaminant free. Optionally, the air can also be filtered tofurther eliminate the potential for contaminant introduction. Ideally,the delivered air is pressurized on demand (e.g., via the air pump), andthus isn't provided via external resources, such as external “shop” airor compressed air sources, which typically contain contaminants such asoil.

The purging device can be implemented using other purging techniques aswell, again with the objective of completely purging the sample from thesample holder while avoiding the introduction of contaminants. Forexample, in one embodiment, the purging device includes a vibratingmechanism instead of (or in some embodiments, in addition to) an airpump. In this embodiment, mechanical vibration or movement is used topurge the sample from the holder (or to supplement the use ofpressurized air for sample removal). Alternatively, purging could beprovided via acoustic or sonic waves imposed on the sample. Othertechniques could also be used, and/or combinations of the foregoingtechniques.

Other embodiments are directed to methods for performing in-process,real time testing of a sample of a material under production, usingsystems of the type described above. For example, in one embodiment themethod would involve the steps of retrieving a sample of a materialbeing produced and placing it in a sample holder at an appropriate pointof the production system. Next, and while production of the materialcontinues, one or more analyzing steps are performed on the sample(e.g., spectroscopy, humidy, particle size, etc.) to evaluate desiredproperties. Once the analysis is completed, the sample is purged fromthe sample holder (or even optionally returned to the productionsystem), such that the analysis is provided in a closed-loop,substantially real-time fashion. For example, if purging occurs viapressurized air, this step of the process might include actuating an airpump with ambient/localized or filtered air until air in a compressionchamber is pressurized to a sufficient level and then purging the sampleby delivering the pressurized air from an outlet of the air pump to anair inlet of the sample holder. The use of ambient and/or filtered airinsures that the purged material, as well as the sample holder, is notcontaminated as a result of the purging step, thereby maintaining theintegrity of the tests performed, and the material being produced.

This Summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This Summary is not intended to identify key features oressential characteristics of the claimed subject matter, nor is itintended to be used as an aid in determining the scope of the claimedsubject matter.

Additional features will be set forth in the description which follows,and in part will be obvious from the description, or may be learned bythe practice of the teachings herein. Features of the invention may berealized and obtained by means of the instruments and combinationsparticularly pointed out in the appended claims. Features of the presentinvention will become more fully apparent from the following descriptionand appended claims, or may be learned by the practice of the inventionas set forth hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic cross-sectional view of a system for analyzing oneor more properties of a sample, according to one embodiment.

FIG. 2 is a schematic cross-sectional view of a peristaltic pump.

FIG. 3A is a schematic cross-sectional view of a sample holder having amovable cover with an aperture for allowing an in-process sample to fallinto the sample well, according to one embodiment.

FIG. 3B is a top perspective view of one embodiment of a cover with avariable sieve retractable lid.

FIG. 3C is a side perspective view of one embodiment of a cover in theclosed position.

FIG. 4A is a top perspective view of a sample holder, according toanother embodiment.

FIG. 4B is a bottom perspective view of a channel in the sample holdershown in FIG. 4A.

FIG. 4C is a cross-sectional view of the sample holder shown in FIG. 4Aalong line A-A.

FIG. 5A is a front perspective view of an air pump, according to oneembodiment.

FIG. 5B is a side perspective view of the air pump shown in FIG. 5A.

FIG. 5C is a cross-sectional view of the air pump shown in FIG. 5A alongline B-B.

FIG. 6 is a flowchart illustrating one example of a method for purging asample.

The figures depict different embodiments for purposes of illustrationonly. One skilled in the art will readily recognize from the followingdiscussion that alternative embodiments of the structures and methodsillustrated herein may be employed without departing from the principlesdescribed herein.

DETAILED DESCRIPTION OF SOME EXAMPLE EMBODIMENTS

Embodiments of the present invention are directed to systems and methodsfor analyzing in-process samples in substantially real time while amanufacturing lot of material is being produced. Such systems andmethods may reduce production time and prevent rejection of expensivebatches of material such as pharmaceuticals, fine chemicals, andspecialty chemicals.

Advantages of the system and methods described herein might include, butare not limited to: (1) providing a self-contained system that isintegrated into the manufacturing line for real-time analysis ofsamples; (2) providing a system having a purging device that is capableof completely purging a sample from a sample holder in a manner thatdoes not introduce contaminants; (3) providing a system that is easilyserviced and cleaned to prevent cross-contamination of subsequentbatches of production material; (4) providing a system in which thecomponents used to purge a sample from a sample well are isolated (orself-contained) from the components used to analyze the sample; (5)providing a system that prevents a sample from entering and damagingother components of the system; and (6) providing a system thatdetermines FDA-acceptable measurements and additional data that allowsthe material to be tested and validated during the actual productionprocess.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contentclearly dictates otherwise. Thus, for example, reference to a samplewell having “an air inlet” includes sample wells having two or more airinlets.

Systems

Referring to FIG. 1, a system 100 for in-process analysis of one or moreproperties of a sample is illustrated. In one embodiment, the system 100is used to analyze one or more properties of a sample e.g., a powder ora liquid sample. The system is installed (or integrated) in a productionline such that a sample of a material may be analyzed in substantially“real-time,” which, as used herein, indicates that the analysis occurswhile the material is being manufactured, produced or otherwiseprocessed. The system 100 includes a self-contained purging device 101configured to purge a material from a sample holder 103, one or moreanalyzers 102 configured to analyze a sample of material in the sampleholder, and a power source (not shown) operably connected to the purgingdevice 101 and one or more analyzers 102.

The sample holder 103 is configured to receive and retain a sample ofthe material during a time period corresponding to the manufacture ofthe material. The one or more analyzers 102 are configured to interactwith the sample contained within the sample holder 103 and to analyze aproperty of the sample during the time period. The purging device 101 isoperatively connected to the sample holder 103 and is configured, asdescribed herein, to purge the sample from the sample holder 103 in amanner such that contaminants are not introduced into the sample holder.

The purging device 101 is “self-contained” or isolated from the one ormore analyzers 102 to prevent the purging device 101 from interfering orcontaminating the one or more analyzers 102. The system 100 may includeone or more programmable controllers (not shown) for controlling each ofthe above components. The system 100 may also optionally include ahousing (housing) to encase and protect the components therein.

FIGS. 1, 2A, 3A-3C and 4A-4C illustrate one embodiment of a purgingdevice 101, here implemented so as to deliver pressurized air so as topurge material contained within a sample holder 103. Pressurized air isdelivered via an air pump 104, as will be described in further detailbelow. Air pump 104 is an example of a source of pressurized air that isselectively delivered to the sample holder 103 so as to purgesubstantially the entire sample from the sample holder 103.

The sample holder 103 includes a body 108 formed of a chemically inertmaterial that may withstand harsh cleaning substances such as detergentand solvents. In one embodiment, the body 108 is formed of stainlesssteel, substantially inert or non-reactive polymeric materials, or anyother material that is suitable to the particular material beingproduced. In the illustrated embodiment, the sample holder 103 furtherincludes a well 110 for retaining a sample. The well 110 includes afirst wall 114 having an air inlet 112, a second wall 116 opposite thefirst wall 114, and a base 118 that permits appropriateaccess/interaction with the sample contained in the well 110 by ananalyzer 102. For example, in one embodiment the base may be formed as awindow that is optically clear, and through which the one or moreanalyzers 102 may analyze the sample via well-known spectrographictechniques, such as by excitation by a laser (not shown). Of course,depending on the analysis being performed, the base may include otherforms so as to provide the appropriate access to the sample.

In the illustrated embodiment, the air inlet 112 is located on the firstwall 114 such that pressurized air may reach the entire upper surface ofthe base 118 and thereby purge the sample from the base 118 and well110. The air inlet 112 may be located on a lower portion of the firstwall 114 and may span the width of the first wall 114. The air inlet 112may be rectangular, circular, elliptical or any other appropriatecross-sectional shape. The first wall 114 of the well 110 may besubstantially perpendicular to the base 118. The second wall 116 mayhave a surface that slopes away from the first wall 114 to facilitateremoval of sample from the well 110. It will be appreciated that theconfiguration of the sample holder 103 might be shaped, sized and/orotherwise implemented in different ways so as to accommodate analternate purging technique. For example, while the embodiment shownhere is optimized for purging of sample material via pressurized air,other purging techniques might dictate differing sample holderconfigurations.

In embodiments illustrated in FIGS. 3A and 3B, the sample holder 103further includes a movable cover 120 that may be used to retain a samplein the well 110. The cover 120 could be a lid, a powder bed, and thelike. In one embodiment, the cover 120 may be actuated by, for example,air or a solenoid (e.g., via a programmable controller or the like). Thecover 120 may be moved such that it uncovers the well 110 to allow thesample into the well 110 as well cover the well 110 to retain the samplein the well 110 or prevent particles from entering the well 110. In someembodiments, the sample holder 103 might include a vibrating mechanismthat facilitates the rate at which particles enter the well 110. Thecover 120 may be pivotally, hingedly or slideably attached to the body108 of the sample holder 103. The cover 120 may be formed of achemically inert material, e.g., stainless steel. In some embodiments,the cover 120 could include a rotating sieve for moving the particlesinto the well.

As illustrated in FIG. 3A, the cover may optionally include an aperture121 smaller in diameter than the opening of the well 110. In these orother embodiments, the cover 120 and the aperture together move acrossthe top of the well 110 so that particles pass through the aperture 121into the well 110. The size of the aperture 121 can act as a filter soas to regulate the size of particles that are allowed to pass into thewell 110. Additionally, the period of time during which the aperture 121is over the well 110 can be varied (e.g., via the programmablecontroller) to vary, or otherwise control, the quantity of the samplethat enters the well 110.

In some embodiments, the cover 120 might include a variable sieve thatallow for particles of varying sizes to enter or leave the well 110. Forexample, FIG. 3B illustrates a top perspective view of an exampleembodiment of a cover 120. In the illustrated embodiment of FIG. 3B, thecover 120 includes one or more first-size apertures 121 a, one or moresecond-size apertures 121 b, one or more third-size apertures 121 c, oneor more fourth-size apertures 121 d, one or more fifth-size apertures121 e, one or more sixth-size apertures 121 f, and one or moreseventh-size apertures 121 g. The apertures 121 a-121 g have differentsizes such that particles of different sizes can be selected for entryinto or out of the well 110. For example, the first-size apertures 121 amay have a diameter of 5 μm such that particles that are 5 μm or smallermay pass through the first-size apertures 121 a; the second-sizeapertures 121 b may have a diameter of 10 μm such that particles thatare 10 μm or smaller may pass through the second-size apertures 121 b;the third-size apertures 121 c may have a diameter of 20 μm such thatparticles that are 20 μm or smaller may pass through the third-sizeapertures 121 c; the fourth-size apertures 121 d may have a diameter of30 μm such that particles that are 30 μm or smaller may pass through thefourth-size apertures 121 d; the fifth-size apertures 121 e may have adiameter of 50 μm such that particles that are 50 μm or smaller may passthrough the fifth-size apertures 121 e; the sixth-size apertures 121 fmay have a diameter of 100 μm such that particles that are 100 μm orsmaller may pass through the sixth-size apertures 121 f; and theseventh-size apertures 121 g may have a diameter of 150 μm such thatparticles that are 150 μm or smaller may pass through the seventh-sizeapertures 121 g. The sizes and/or number of aperatures may varydepending on the needs of a given application, and the above-listedsizes and number of apertures is merely one example.

As mentioned above, the cover 120 of FIG. 3B may be configured tointerface with the well 110 of FIG. 3A such that different particlesizes are selected for entry into (or exit from) the well 110. FIG. 3Cillustrates an example of the cover 120 of FIG. 3B positioned over thewell 110. In the illustrated example of FIG. 3C, the cover 120 is in aclosed position and can be moved selectively to the left such thatspecific apertures 121 of a desired size are positioned over the well110, again, for example, under programmable control. Therefore,particles of a corresponding size are allowed into the well 110. Thecover 120 can be moved back to the closed position once a desired amountof sample is deposited in the well 110.

If an application requires particles of most sizes to be deposited inthe well 110, a larger aperture size, e.g., aperture 121 g, can bepositioned over the well. In this example, particles having a diameterof 150 μm or smaller will be allowed to pass into the well 110.Alternatively, or in addition, the cover 120 can be positioned such thatsmaller apertures 121 are positioned over the well 110. Compressed aircan be pumped into the well 110 (e.g., via the pump 104) such thatparticles the same size as or smaller than the smaller apertures 121exit the well 110 and larger particles are retained in the well 110.

Returning to FIG. 3A, in one embodiment, pressurized air is pumpedthrough tubing 301 to the well 110. An incoming valve 302 going into thewell 110 can be selectively opened (e.g., via programmable controller)to allow the air to pass through while keeping the exhaust valve 303closed. This causes a disruption of sample particles to blow aroundinside the well 110. The analyzer 102 reads the well 110 continuously toaverage the Raman signal over about 100 mg. In some embodiments, theanalyzer 102 integrates the signal instead of scanning the well 110. Thepump 104 is turned off to let the particles settle. The analyzer 102images the isolated particles. The analyzer 102 can use low numericalaperture (NA) optics, which may advantageously help create an averagevalue over the sample.

Once the particles have been analyzed, a programmable controller or auser can open the exhaust valve 303 to purge the particles to theelutriation waste container 304. In some embodiments, the elutriationwaste container 304 could also include a negative pressure mechanism forfurther clearing the particles from the well 110. Alternatively, theparticles could be blown back into the feed frame and reintroduced intothe production system. The waste container 304 can also contain arelease valve 306 for releasing pressure generated by the pump 104through the system that is covered by a filter 307 to prevent theparticles from escaping.

In another embodiment, the system 100 in FIG. 1 may analyze crystalsfrom fluid using a liquid purge with peristaltic pump. In oneembodiment, the system 100 includes a well 110 where the crystals settleon a window such as the base 118 illustrated in FIG. 1 by gravity,centrifuge, electrostatic, or another attraction. The base 118 istransparent for viewing or otherwise detecting the crystals.

Since the distribution of crystals may be sparse, it is advantageous tohave a well 110 with scanning capability under such circumstances.During operation, once the crystals have settled, the presence orconcentration of the crystals can be analyzed using optical imaging,spectroscopic analysis, other techniques or a combination thereof. Thepump can then be used to cause the fluid to flow over the window,thereby displacing the settled crystals. Once the crystals are displacedby the flow from the pump, the process may be repeated, as crystals froma subsequent sample settle onto the window 110.

In some embodiments, the system 100 includes a camera for capturing animage sparse field. The analyzer 102 in FIG. 1 analyzes the crystals. Inone embodiment, the analyzer 102 identifies particles for imageanalysis. For example, the analyzer 102 performs an XY Raman scan ofparticles to identify composition and crystal morphology. This may bethrough direct Raman excitation to each particle to measure it. Theanalyzer 102 uses the image and any other information to analyze crystalsize, shape, composition, etc.

Turning to FIG. 2, the pump 104 of FIG. 1 may be a peristaltic pump 280for use in an environment in which the particles to be measured ordetected are contained in a liquid. The peristaltic pump 280 has theadvantage that fluid from the manufacturing process and fluid from theinstruments do not come into contact with each other, thereby avoidingcontamination. The peristaltic pump 280 is used with liquid in areaction or crystallization vessel 260 in this embodiment. The liquidincludes crystals 270 or other reaction particles. The liquids feed intothe peristaltic pump 280. The pump 280 displaces crystals aftermeasurement, for example, using compressing tubing 290 that may bedisposable. It is noted that the specific examples presented herein inthe context of crystals in a liquid are more generally applicable toother operating environments. For example, the target material of themeasurement process is allowed to settle from a fluid (i.e., liquid, airor another gas) onto the window. The material is then measured using thetechniques described herein, and the pump is used to remove the measuredmaterial from the window and to allow material from a subsequent sampleto settle onto the window to repeat the measurement process.

Returning now to an example of operation in the context of samples to bemeasured from an atmospheric environment, the air pump 104 of FIG. 1 isin fluid communication with the air inlet 112 of the well 110 in thesample holder 103. A connector 122 connects an outlet 124 of the airpump 104 to a channel 126 in the body 108 of the sample holder 103. Inone embodiment, the connector 122 is a flexible tube formed from one ormore chemically inert materials, such as silicone, PVC, polyurethane,fluoropolymers and/or thermoplastic elastomers. The channel 126 providesa passage through which the pressurized air may be delivered to the airinlet 112 of the well 110. The channel 126 may be curved or may have aturn 128 or an elbow having a first segment 130 angled at about 90 to135 degrees relative to a second segment 132. For example, in the sampleholder embodiment shown in FIGS. 1, 2, and 4C, the angle between thefirst and second segments 130 and 132 of the channel 126 is about 90degrees. In one embodiment, the size (i.e., cross-section) of thechannel 126 may be uniform from the connector 122 to the air inlet 112.In another embodiment, the size of the channel 126 may vary from theconnector 122 to the air inlet 112, i.e., the channel 126 may taper insize from a small to large size or from a large to small size. Inanother embodiment, the shape of a cross-section of the channel 126 maychange along the length of the channel 126, e.g., the cross section maychange from circular to rectangular in shape or from rectangular tocircular in shape. Again, cross-sectional shapes and/or sizes might beselected depending on the air-flow dynamics required to effect properpurging of a given material sample from the well of the sample holder.

Referring again to FIG. 1, the air pump 104 of the purging device 101 isconfigured to deliver pressurized air to the air inlet 112 in the well110. An exemplary embodiment of an air pump 104 that may be used in thesystem 100 is illustrated in FIGS. 5A-5C. In this example, the air pump104 is linearly actuated and includes a self-lubricating piston ratherthan requiring oil lubrication which may contaminate production batchesof material. The air pump 104 includes a drive mechanism having a motor240 and one or more drive components (e.g., a screw-driven drive shaft242) operably connected to a piston 244 in a reservoir 246 having one ormore seals 247. Exemplary motors include a DC, a stepper or a solenoidmotor. The motor may be powered by an external power source or abattery. In one embodiment, the piston 244 is formed from graphite andis self-lubricating. The air pump 104 may optionally be mounted on asupport 248.

In the illustrated example, the air pump 104 further includes an airintake 250 having an air intake control valve 252 and an outlet 124 (orexhaust) having an outlet control valve 256. The air intake 250 mayoptionally include one or more filters for filtering out impurities inthe air (i.e., ambient air) entering the pump 204. The outlet 124 is influid communication with the air inlet 112 of the sample holder 103 andmay optionally include one or more filters. In an embodiment, the airintake control valve 252 and the outlet control valve 256 aresolenoid-controlled pinch valves and are operated under programmablecontrol via a controller (not shown).

The air pump 104 further includes a compression chamber 258 (see FIG.5C) and an optional pressure sensor 260 that may be attached to an exitport 262 in the compression chamber 258. In an embodiment, the pressuresensor 260 is attached to the exit port 262 of the compression chamber258 by, for example, a flexible tube. The pressure sensor 260 can bemonitored via a controller so as to insure sufficient air pressure isavailable for purging of the material sample contained in the sampleholder.

In another embodiment (not shown), a peristaltic pump may be used todeliver pressurized air to the air inlet 112 through tubing. Anadvantage of a peristaltic pump is that only the inner surface of thetubing comes into contact with the pressurized air which minimizescontamination of the air delivered to the inlet 112. Also, the air pumpmechanism is protected from damage by ingress of a sample through thetubing.

While in the illustrated embodiment the purging device is configured soas to effect purging of the sample by way of pressurized air, it will beappreciated that other purging mechanisms could also be employed. Forexample, the pump 104 could be replaced with (or supplemented by) adevice that causes the material to vibrate. The vibrating device couldbe located where the pump currently is or more directly beneath the well110. Acoustic or sonic vibrations might also be employed to evacuatematerial from the sample holder. The purging can be performed orsupplemented in certain embodiments using a mechanical transportation ofthe material from the well 110. The purging of the material from thewell 110 can alternatively be facilitated using gravity by configuringthe well 110 such that it is movable into a position from which thematerial can fall therefrom. In such embodiments, the various techniquesfor purging the material can be used in combination with an air pump.

Referring again to FIG. 1, the one or more analyzers 102 are located inclose proximity to the base 118 of the well 110 such that the sample maybe analyzed through the base 118. In an embodiment, the one or moreanalyzers 102 are located below the base 118. In another embodiment, theone or more analyzers 102 are coupled to the well 110 with relay opticsor fiber optics. Exemplary analyzers 102 include, but are not limitedto, a Raman spectrometer, a near infrared (NIR) spectrometer, a camera,an imaging particle analyzer and/or a differential calorimeter. Otheranalyzer types can also be employed, depending, for example, on thematerial under test and/or the types of tests needed.

Methods

In operation, the purging device 101 of the system 100 may be used topurge a sample from a well 110 after the sample is analyzed with one ormore analyzers 102. In an exemplary method, an in-process sample from abatch of material being manufactured is placed into the well 110. Thesample may, for example, fall into the well 110 by gravity as the batchof material moves past the well 110. In another example, the sample mayfall into the well 110 through a sieve in the cover 120 or an aperturein the cover 121. This process may be facilitated via a vibrating deviceor by imposing negative pressure on the well 110. One or more propertiesof the sample are then analyzed. Both an outlet 124 and an air intake250 of a pump 104 are closed, for example, via an input valve 302. Inone embodiment, the air pump 104 of the air purging device 101 isactivated by moving a piston 244 to an extended position until air in acompression chamber 258 is pressurized to a desired level, which can bemonitored via pressure sensor 260. In another embodiment, a vibratingdevice causes the well 110 to vibrate. In some embodiments, the methodresults in an accurate active pharmaceutical ingredients (API)percentage in about 100 milliseconds (ms) to 1 second depending on howlong the purging step below takes.

In one embodiment, after analysis is complete the sample is removed orpurged from the well 110 by releasing pressurized air through the outlet124 of the air pump 104 and delivering the pressured air to the airinlet 112 of the well 110. In another embodiment, the sample is purgedby opening the exhaust valve 303 and activating the vibrating device.The purged sample may be added back to the batch of material beingmanufactured or disposed of in an elutriation waste container 304. In anembodiment, the release of pressured air through the outlet 124 can becontrolled via activation of an outlet control valve 256. In anembodiment, air is delivered to the air inlet 112 at a suitable gas flowrate for a period of time (e.g., for one or more seconds to one or moreminutes) until the sample is purged from the well 110. In anotherembodiment, modulated air is delivered to the air inlet 112 such thatthe gas flow rate is varied over a time period, e.g., for one or moreseconds to one or more minutes. In another embodiment, one or morepulses of pressurized air are delivered to the air inlet 112 such thatthe pressurized air is cycled on and off one or more times. Afterremoving the sample from the well 110, the pump outlet 124 is closed andthe air intake 250 of the pump is opened to allow ambient air or a gassuch as nitrogen or argon to enter the reservoir 246 of the air pump 104as the piston 244 is moved back to a start position. Ambient air i.e.,air that is local to the analysis system, is used instead of factory airwhich may have contaminants such as oil or particulates. The ambient airmight also be filtered to further insure elimination of anycontaminants. In this way, a material sample is completely purged fromthe sample container. Moreover, since elimination of the sample occursin a manner that does not introduce contaminants into the samplecontainer, further and continued analysis can be performed in-processand in substantially real-time. In this way, continuous and accurateanalysis data can be obtained while the material is being produced. Assuch, corrective action can be taken as problems are detected, therebyreducing waste and production times.

In another exemplary method, a sample well 110 having a movable cover120 (shown in FIGS. 2 and 3) is used with the system 100 to analyze anin-process sample from a manufacturing lot of material. In thisembodiment, the air pump might also be used as a blower to mix oragitate a powder or liquid sample retained in a covered well. As thebatch of material moves past the sample well 110, a measured amount ofsample is deposited in the sample well and the movable cover is movedover an opening of the sample well or the sample is deposited throughone or more apertures in the cover which is then moved so that a solidregion of the cover is positioned over the opening of the sample well.Pressurized air is delivered to the sample well 110 such that the sampleis mixed or agitated for a predetermined amount of time, such as about100 ms. The sample is analyzed for one or more properties while beingmixed. The sample may optionally be allowed to settle and then may bere-analyzed for one or more properties. After analyzing the sample, thesample may be sent (purged) to waste or may be added back to the batchof material moving past the sample well 110 as described above. Thismethod may be used to measure the average properties of the sample,e.g., the Active Pharmaceutical Ingredient percent.

In an embodiment in which a small amount of a powdered sample isintroduced into the covered well, individual particles may be analyzedand sized. In yet another embodiment, a liquid sample may be introducedto a sample well 110 with a cover 120. In this embodiment, air bubblesare introduced into the liquid sample and the velocity of the bubblesmay be used to determine viscosity of the liquid sample.

Turning now to FIG. 6, a flowchart 600 illustrating one example of aseries of steps for purging a sample of material during a manufacturingprocess is illustrated. A sample is placed 602 in a sample holder 103that is configured to receive and retain the sample during themanufacture of the material. In this particular illustration, the sampleholder includes an optically clear base so as to accommodate analysisvia, for example, spectrographic techniques. One or more properties ofthe sample are then analyzed, as is denoted at step 604. For example, ananalyzer 102 could determine a percentage of active ingredients in thesample via spectrographic techniques.

Once analysis is complete, and while manufacture of the materialcontinues, at process step 606 an air pump is actuated until air in acompression chamber is pressurized to a predetermined pressure (i.e.,sufficient to evacuate the sample contained within the holder). As isrepresented at step 608, the sample is purged from the sample holder 103by delivering pressurized air from an outlet 124 of the air pump 104 tothe air inlet 112 of the sample holder 103. In some embodiments, thepurged sample is collected in an elutriation waste container 304 or byreintroducing the sample back into the production system.

While the foregoing example process is described in the context of apurging device provided via pressurized air, alternate purgingtechniques could also be used in lieu of (or as a supplement to)pressurized air. Also, while not shown here, optional process stepsmight be added. For example, to facilitate analysis of the sample,pressurized air might be delivered to the sample holder to disturb thesample material in an appropriate manner.

Where methods and steps described above indicate certain eventsoccurring in certain order, those of ordinary skill in the art willrecognize that the ordering of certain steps may be modified and thatsuch modifications are in accordance with the variations of theinvention. Additionally, certain of the steps may be performedconcurrently in a parallel process when possible, may be performed inreverse order when possible and may be performed sequentially asdescribed above.

Although the detailed description contains many specifics, these shouldnot be construed as limiting the scope of the invention but merely asillustrating different examples and aspects of the invention. It shouldbe appreciated that the scope of the invention includes otherembodiments not discussed in detail above. Various other modifications,changes and variations which will be apparent to those skilled in theart may be made in the arrangement, operation and details of the methodand apparatus of the present invention disclosed herein withoutdeparting from the spirit and scope of the invention as defined in theappended claims. Therefore, the scope of the invention should bedetermined by the appended claims and their legal equivalents.

1-25. (canceled)
 26. A system for analyzing a property a sample fromcontinuous production process, wherein the system comprises: a sampleholder comprising a window, wherein the sample holder is configured toreceive a sample from a continuous production process; a spectroscopicanalyzer operatively coupled to the window, wherein the spectroscopicanalyzer is configured to determine a property of the sample; and apurge device operatively coupled to the sample holder and configured toexpunge the sample from the sample holder.
 27. The system of claim 26,wherein the sample comprise particles, crystals, or a combinationthereof.
 28. The system of claim 26, wherein the sample comprisespharmaceutical powder, fine chemicals, specialty chemicals, or acombination of any of the foregoing.
 29. The system of claim 26, whereinthe sample comprises proteins, DNA, or whole cells.
 30. The system ofclaim 26, wherein the sample comprises a material, and the spectroscopicanalyzer is configured to determine a property of the material.
 31. Thesystem of claim 26, wherein the sample holder comprises a well, and asample inlet coupled to the well, wherein the window is disposed withinthe well.
 32. The system of claim 31, wherein the well is configured totemporarily retain the sample.
 33. The system of claim 31, wherein thesample holder comprises a moveable cover configured to temporarily coverthe well.
 34. The system of claim 33, wherein the moveable coverpivotally, hingedly, or slideably attached to the body of the sampleholder.
 35. The system of claim 31, wherein the well comprises a purgeinlet, wherein the purge device is coupled to the purge inlet.
 36. Thesystem of claim 32, wherein the well comprises an outlet.
 37. The systemof claim 26, wherein the purging device comprises an apparatusconfigured to generate pressurized air, vibrations, acoustic energy,ultrasonic energy, or a negative pressure.
 38. The system of claim 26,wherein the purging device comprises a pressurized air pump.
 39. Thesystem of claim 26, wherein the purging device comprises a peristalticpump.
 40. A manufacturing process comprising the system of claim
 26. 41.The manufacturing process of claim 39, wherein the manufacturing processcomprises a continuous flow of material, and the sample holder isoperatively coupled to the continuous flow of material.
 42. Themanufacturing process of claim 40, wherein the continuous flow ofmaterial comprises pharmaceutical powder, fine chemicals, specialtychemicals, or a combination of any of the foregoing.
 43. A method ofanalyzing a sample of material in a continuous production process,comprising: providing a continuous flow of material and the system ofclaim 26, wherein the sample holder is operatively coupled to thecontinuous flow of material; obtaining a sample of material from thecontinuous flow of material in the sample holder; spectroscopicallyanalyzing the sample of material; and purging the sample of materialfrom the sample holder.